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Abstract:
Single subcutaneous injections of 1,2-dibromo-3-chloropropane (DBCP) produced dose-dependent injury to the kidney, testis, epididymis and liver of male, Fischer 344 rats. Pretreatment with the enzyme inducer phenobarbital reduced the nephrotoxic potency of DBCP. Serum creatinine and urea nitrogen concentrations were lower, and renal proximal tubular necrosis was less severe in phenobarbital pretreated than in non-pretreated rats subsequently injected with various amounts of DBCP. 3-Methylcholanthrene (3-MC) or cobaltous chloride (CoCl2) pretreatments enhanced the dose-dependent necrogenic effects of DBCP on the kidney and, in general, potentiated the DBCP-induced elevations of serum creatinine and urea nitrogen concentrations. Pre- and post-treatment with the enzyme inhibitor piperonyl butoxide had no discernable effect on the nephrotoxic potency of DBCP. The hepatotoxic potency of DBCP, as measured by elevations in the serum activities of glutamic pyruvic transaminase (GPT) and sorbitol dehydrogenase (SDH), and by histological analysis of the severity of centro lobular necrosis, was prevented or quantitatively reduced by phenobarbital pretreatment. 3-MC, CoCl2 or piperonyl butoxide pretreatments had no consistent effect on DBCP hepatotoxicity. The dose-dependent seminiferous tubular atrophy induced in rats by DBCP was enhanced by CoCl2 and reduced by phenobarbital. Cobalt chloride pretreatment also enhanced the DBCP-induced degeneration of the epithelium of the caput (head) epididymis, while phenobarbital blocked or reduced this effect. Neither 3-MC nor piperonyl butoxide consistently altered the gonadotoxic potency of DBCP. Cobalt chloride also enhanced, while phenobarbital reduced, the acute lethal potency of DBCP. Single-treatment, subcutaneous LD50 values for DBCP were 102 mg/kg in non-pretreated and 128 mg/kg in phenobarbital pretreated rats. The potency ratio (0.796; confidence interval, 0.728-0.871) was statistically significant (P less than 0.05). The modulating effects of CoCl2 and phenobarbital could not be ascribed simply to changes in tissue concentrations of the protective conjugation substrate glutathione, since CoCl2 increased and phenobarbital did not alter renal and hepatic non-protein sulfhydryl concentrations. These data indicate a complex role of metabolism in determining dose-dependent toxic response to DBCP administration.
Insights
This study shows that pretreatments with phenobarbital or cobaltous chloride significantly alter the toxicity of 1,2-dibromo-3-chloropropane (DBCP) in rats. Phenobarbital reduced DBCP toxicity, while cobaltous chloride enhanced it, indicating a complex role for metabolism in toxic responses.
Area of Science:
- Toxicology
- Pharmacology
- Biochemistry
Background:
- 1,2-dibromo-3-chloropropane (DBCP) is a chemical with known toxic effects.
- The role of metabolic enzymes in modulating DBCP toxicity is not fully understood.
Purpose of the Study:
- To investigate the effects of enzyme inducers and inhibitors on DBCP-induced toxicity in male Fischer 344 rats.
- To elucidate the complex role of metabolism in determining dose-dependent toxic responses to DBCP.
Main Methods:
- Single subcutaneous injections of DBCP were administered to male Fischer 344 rats.
- Rats were pretreated with enzyme inducers (phenobarbital, 3-methylcholanthrene) or inhibitors (piperonyl butoxide, cobaltous chloride).
- Toxicity was assessed by measuring serum creatinine, urea nitrogen, liver enzymes (GPT, SDH), and histological examination of kidney, liver, testis, and epididymis.
Main Results:
- Phenobarbital pretreatment reduced nephrotoxicity and hepatotoxicity of DBCP, and also reduced seminiferous tubular atrophy and epididymal degeneration.
- Cobaltous chloride pretreatment enhanced DBCP-induced kidney damage, seminiferous tubular atrophy, and epididymal degeneration.
- Phenobarbital pretreatment significantly increased the subcutaneous LD50 of DBCP, indicating reduced acute lethal potency.
Conclusions:
- Metabolism plays a complex role in the dose-dependent toxicity of DBCP.
- Enzyme induction and inhibition can significantly modulate the toxic effects of DBCP on various organs.
- These findings have implications for understanding and mitigating DBCP-induced toxicity.